Embodiments of the invention are directed generally to the field of medicine. Certain embodiments are directed to the field of oncology and cancer therapeutics.
Recent therapeutic strategies to combat immune-derived diseases have focused on T-cell signaling pathways and the molecules that comprise them. T-cell signaling cascades and their potential role as molecular targets for the treatment of immunoflammatory disease like rheumatoid arthritis, inflammatory bowel disease, psoriasis, and for the prevention of transplant rejection are described in “Drugs RD, 2010; 10(4)” comprehensive review.
Complete activation of T-cells requires three threshold-limited sequential signals. A first signal delivered by antigens that engage a specific T-cell receptor (TCR) is followed by a second signal delivered by a B7/CD28 interaction. Within seconds to minutes after TCR engagement, the CD3ζ chain is tyrosine (Tyr) phosphorylated during the autoactivation of Zap70, Lck, and Fyn protein Tyr kinases. Concomitantly, calcium (Ca2+) mobilization triggers catalytic activation of CaN phosphatase to dephosphorylate nuclear factor of activated T-cell (NFAT)—a necessary step for NFAT to translocate to the nucleus and bind discrete DNA binding elements within the promoter of the interleukin (IL)-2 gene. The first and second signals are critical for the synthesis and secretion of IL-2, which, in concert with other T-cell growth factors (TCGFs) such as IL-4, -7, -9, -13, -15 and -21, deliver a third signal through cytokine receptors, a necessary step required to drive clonal expansion of T-cells. These cytokine receptors share a common γ chain (γe) that when combined with a unique α-chain for each cytokine deliver intracellular signals via Janus tyrosine kinase (JAK) JAK1 and JAK3, as well as activate signal transducers and activators of transcription (Stat) Stat1, Stat3, Stat5a/b and Stat6.
Unlike other signaling pathway molecules that serve as candidate targets for therapeutic intervention, JAK3 expression shows a limited pattern of tissue expression and is compartmentalized to T-cells, B-cells, natural killer (NK) cells and monocytes, or in general terms to cells of immune origin. Because of the involvement of JAK3 in T-cell activation and proliferation, and the documented genetic evidence for the role of JAK3 in autoimmune or transplant-induced inflammatory disorders, the selective targeting of JAK3 in T-cells may potentially be clinically beneficial in T-cell-derived pathologic disorders. Recently, JAK3 activation has been reported in several lymphoid malignancies, including cutaneous T-cell lymphoma, anaplastic large cell lymphoma mantle-cell lymphoma, HTLV-1-induced adult T-cell leukemia, Burkitt lymphoma, and acute lymphoblastic leukemia. Thus, JAK3 is a viable molecular target in the treatment of immune-mediated diseases and a broad range of hematopoietic cancers. These malignancies represent an aggressive subset of blood cancers and despite advancement in the treatment of these cancers, patients who do not respond to standard therapy or relapse face a very poor prognosis. Thus, there is a need for additional therapies and compounds to address these unmet medical needs.